1. Field of the Invention
The present invention relates to anti-CD147 antibodies and their use as therapeutics.
2. Related Art
CD147 is a member of the immunoglobulin (Ig) superfamily that is expressed on a large number of different cells in a variety of tissues. It was originally named human Basigin (for basic immunogloblin superfamily) and was first cloned in about 1991. (Miyauchi et al. J Biochem (Tokyo) 110:770-774 (1991); Kanekura et al. Cell. Struct Funct 16:23-30 (1991); Miyauchi et al. J Biochem (Tokyo) 110:770-774 (1991)). The bsg gene product, CD147, also known as EMMPRIN (Extracellular Matrix Metalloprotein Inducer”) isoform II (NCBI Accession No. NP—940991) is a propolypeptide 269 amino acids in length (SEQ ID NO: 1, FIG. 1), having a signal peptide 22 or 24 amino acids in length, a 183 amino acid extracellular domain, a transmembrane domain from residues 208-228, and an intracellular domain from residue 229 to the 269th residue. According to the curated NCBI record, the extracellular domain (ECD) is comprised of two immunoglobulin-like domains: a C2-type domain from residue 22 to 103 and a V-like domain from residue 105-199 (FIG. 1). A number of splice variants have also been reported.
CD147 is a pleiotropic molecule playing a role in fetal development, retinal function, and in T-cell maturation. It has been shown to be a cell-surface receptor for cyclophilins. It is expressed in areas of tissue remodeling: tumors, endometrium, placenta, skin and regions undergoing angiogenesis (See Iacono et al. 2007. Exp Mol. Path 83:283-295) and stimulates matrix metalloproteinases (MMPs) and VEGF production. CD147 is induced upon monocyte differentiation and is expressed in human atheroma (Major T C, Liang L, Lu X, Rosebury W, Bocan T M. 2002. Arterioscler Thromb Vasc Biol. 22: 1200-1207). It has been shown that CD147 promotes invasion and metastasis in different tumor types via the induction of matrix metalloproteinases (MMPs) and the urokinase-type plasminogen activator system by peritumoral stromal cells. CD147 is also involved in angiogenesis, anoikis resistance, lactate efflux, multidrug resistance, and cell proliferation in cancer cells. CD147 overexpression and/or function has been associated with other pathological processes such as inflammatory responses, pulmonary fibrosis, rheumatoid arthritis, lupus erythematosus, heart failure, Alzheimer's disease and the infectivity cycle of the human immunodeficiency virus and coronaviruses in lymphocytes. (see Ruiz et al, J. Biol. Chem., Vol. 283, (9), 5554-5566, 2008). In addition, cleavage of CD147 and shedding of CD147 fragments may be involved in CD147 regulation or release of active fragments (Egawa et al. 2006 J Biol Chem 281(49): 37576-85).
Anti-CD147 antibodies have been reported. A murine antibody IgM mAbs, CBL1 (Billings et al. Hybridoma 1:303-311, 1982, U.S. Pat. Nos. 5,330,896 and 5,643,740), was tested in steroid-refractory acute graft-versus-host disease (Heslop et al. The Lancet 346: 805-806; Deeg et al. 2001 Blood 98:2052-8). Human equivalent mAbs binding to epitopes overlapping that of CBL1 (aka ABX-CBL), near the transmembrane domain of the ECD were also developed (US2007048305A1). Koch et al. (Internat Immunol 11(5) 777-786, 1999) mapped CD147 epitopes associated with T- and B-cell activation, reporting that only the highest affinity monoclonal antibody (MEM-M6/6) of a group of antibodies made to CD147 was effective in preventing human T-cell activation and proliferation by the mAbs against CD3, OKT3. A murine antibody to tumor cell derived human CD147, EIIF4 (Ellis, 1989 Cancer Res 49:3385-91; Biswas et al. Cancer Research 55, 434-439, 1995), demonstrated the ability to block lung carcinoma CD147 induced collagenase (matrix metalloproteinase-1 or MMP-1) activity from human fibroblasts. Binding of EIIF4 antibody to CD147 was shown to be abolished when a mutant ECD missing the N-terminal Ig domain was prepared (Biswas, C. et al., Cancer Res 55, 434-439, 1995). Ku et al. (Scan J Immunol 65(5) 435-443, 2007) identified mAbs described as inhibitory for the CD147 associated MMP axis and, by using truncated CD147 sequences, identified key residues at the N-terminus (22A to 50V—SEQ ID NO.: 1) for CD147 MMP induction activity.
Thus, while certain antibodies and other antagonists of CD147 are known, how the complex nature of the protein, including the two immunoglobulin domains, influences the myriad biological activities has not been thoroughly illucidated. Domain specific antagonists may prove to be useful therapeutic candidates for treating various of the pathologies associated with CD147 display and/or activation on various tissues. For example, therapeutic agents capable of blocking production MMPs or VEGF activity induced by CD147 could be advantageous in cancer therapy.
Accordingly, there is a need to provide human antibodies specific for human CD147 for use in therapy to diminish or eliminate symptoms of CD147-dependent diseases, as well as improvements over known antibodies or fragments thereof.